XEN-101

Approach

XEN-101

XEN-101, Xeno's lead product candidate, is an oral-pill formulation designed to deliver molecular oxygen to the lower gut, and thereby mimic the microbiome shift and weight loss induced by Roux-en-Y Gastric Bypass (RYGB) surgery.

(6) Construction of an unhindered, low pressure route from the esophagus to the small bowelleads to weight loss regardless of GI surgery type.

Roux-en-Y gastric bypass (RYGB)

Mini-gastric bypass (MGB)

Billroth I

Billroth II

Total gastrectomy

(7) Proximal bypass or resection of the small intestine (without bypass of the stomach) does not lead to significant weight loss or change in gut microbiome, despite causing exaggerated post-prandial release of incretins (GLP-1, PYY etc.).

Duodenal-jejunal Bypass (DJB)

Ileal transposition (IT)

Jejunum-ileum circuit

Bile diversion to jejunum

Partial jejunal diversion

Small intestinal resection (<50%)

(8) Mechanical restriction of food intake or malabsorption are not the drivers of RYGB weight loss.

Roux-en-Y gastric bypass (RYGB) surgery is one of the most effective treatments for obesity and type II diabetes. RYGB was originally believed to work by mechanically restricting caloric intake or causing macronutrient malabsorption. However, it is now understood that such mechanical effects are not responsible for the remarkable efficacy of gastric bypass. Instead, mounting evidence shows that altered gut neuroendocrine signaling drives all the weight reducing effects of RYGB:

Evers, Simon S., Darleen A. Sandoval, and Randy J. Seeley. "The physiology and molecular underpinnings of the effects of bariatric surgery on obesity and diabetes." Annual Review of Physiology (2016).

Strong Evidence for Air Hypothesis: Gastro-Gastric Fistula (GGF)

Upper GI series in a patient with weight regain (Red arrow: GGF)

A rare complication of RYGB is gastro-gastric fistula (GGF), which is a small fistulous connection spontaneously formed between the old stomach (GR) and the new stomach pouch (GP) post-surgery.

GGF leads to weight regain or prevents weight loss in majority of cases, and surgical closure of GGF restores weight loss. GGF reverses the weight loss effect of RYGB despite the fact that GGF anatomy is effectively the same as normal RYGB anatomy, except for a small connection between the new and the old stomach. In RYGB patients with GGF, majority of ingested food still flows through the correct path (Roux limb) as the fistula is usually situated at the apex of gastric pouch and is very small. Yet, the weight loss efficacy of the surgery is abolished (example case report).

Air hypothesis can explain this phenomenon. With a GGF, swallowed air can flow through the small fistula and get stored in the large (bypassed) stomach, instead of flowing into the small bowel (see below figure).